FOR SUBCUTANEOUS USE ONLY
DESCRIPTION
Ganirelix Acetate Injection is a synthetic decapeptide with high antagonistic activity against
naturally occurring gonadotropin-releasing hormone (GnRH). Ganirelix Acetate is derived from
native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, 8, and 10 to form the
following molecular formula of the peptide: N-acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-Dphenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-N9,N10-diethyl-D-homoarginyl-L-leucylN9,N10-diethyl-L-homoarginyl-L-prolyl-D-alanylamide acetate. The molecular weight for
Ganirelix Acetate is 1570.4 as an anhydrous free base. The structural formula is as follows:
Ganirelix Acetate
Ganirelix Acetate Injection is supplied as a colorless, sterile, ready-to-use, aqueous solution
intended for SUBCUTANEOUS administration only. Each sterile, prefilled syringe contains
250 mcg/0.5 mL of Ganirelix Acetate, 0.1 mg glacial acetic acid, 23.5 mg mannitol, and water
for injection adjusted to pH 5.0 with acetic acid, NF and/or sodium hydroxide, NF.
CLINICAL PHARMACOLOGY
The pulsatile release of GnRH stimulates the synthesis and secretion of luteinizing hormone (LH)
and follicle-stimulating hormone (FSH). The frequency of LH pulses in the mid and late
follicular phase is approximately 1 pulse per hour. These pulses can be detected as transient rises
in serum LH. At midcycle, a large increase in GnRH release results in an LH surge. The midcycle
LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the
oocyte, and luteinization. Luteinization results in a rise in serum progesterone with an
accompanying decrease in estradiol levels.
1
Ganirelix Acetate acts by competitively blocking the GnRH receptors on the pituitary
gonadotroph and subsequent transduction pathway. It induces a rapid, reversible suppression of
gonadotropin secretion. The suppression of pituitary LH secretion by Ganirelix Acetate is more
pronounced than that of FSH. An initial release of endogenous gonadotropins has not been
detected with Ganirelix Acetate, which is consistent with an antagonist effect. Upon
discontinuation of Ganirelix Acetate, pituitary LH and FSH levels are fully recovered within
48 hours.
Pharmacokinetics
The pharmacokinetic parameters of single and multiple injections of Ganirelix Acetate Injection
in healthy adult females are summarized in Table I. Steady-state serum concentrations are
reached after 3 days of treatment. The pharmacokinetics of Ganirelix Acetate are doseproportional in the dose range of 125 to 500 mcg.
TABLE I: Mean (SD) pharmacokinetic parameters of 250 mcg of Ganirelix Acetate following a
single subcutaneous (SC) injection (n=15) and daily SC injections (n=15) for seven days.
Ganirelix Acetate
single dose
Ganirelix Acetate
multiple dose
tmax
t1/2
Cmax
AUC
Vd
†
CL
F
tmax
h
1.1 (0.3)
t1/2
h
12.8 (4.3)
Cmax
ng/mL
14.8 (3.2)
AUC
ng•h/mL
96 (12)
CL/F
L/h
2.4 (0.2)†
Vd/F
L
43.7 (11.4)†
1.1 (0.2)
16.2 (1.6)
11.2 (2.4)
77.1 (9.8)
3.3 (0.4)
76.5 (10.3)
Time to maximum concentration
Elimination half-life
Maximum serum concentration
Area under the curve; Single dose: AUC0–; multiple dose: AUC0–24
Volume of distribution
Based on intravenous administration
Clearance = Dose/AUC0–
Absolute bioavailability
Absorption
Ganirelix Acetate is rapidly absorbed following subcutaneous injection with maximum serum
concentrations reached approximately one hour after dosing. The mean absolute bioavailability
of Ganirelix Acetate following a single 250 mcg subcutaneous injection to healthy female
volunteers is 91.1%.
Distribution
The mean (SD) volume of distribution of Ganirelix Acetate in healthy females following
intravenous administration of a single 250-mcg dose is 43.7 (11.4) liters (L). In vitro protein
binding to human plasma is 81.9%.
Metabolism
Following single-dose intravenous administration of radiolabeled Ganirelix Acetate to healthy
female volunteers, Ganirelix Acetate is the major compound present in the plasma (50–70% of
total radioactivity in the plasma) up to 4 hours and urine (17.1–18.4% of administered dose) up
to 24 hours. Ganirelix Acetate is not found in the feces. The 1–4 peptide and 1–6 peptide of
Ganirelix Acetate are the primary metabolites observed in the feces.
2
Excretion
On average, 97.2% of the total radiolabeled Ganirelix Acetate dose is recovered in the feces and
urine (75.1% and 22.1%, respectively) over 288 h following intravenous single dose
administration of 1 mg [14C]-Ganirelix Acetate. Urinary excretion is virtually complete in 24 h,
whereas fecal excretion starts to plateau 192 h after dosing.
Special Populations
The pharmacokinetics of Ganirelix Acetate Injection have not been determined in special
populations such as geriatric, pediatric, renally impaired and hepatically impaired patients (see
PRECAUTIONS).
Drug-Drug Interactions
Formal in vivo or in vitro drug-drug interaction studies have not been conducted (see
PRECAUTIONS). Since Ganirelix Acetate can suppress the secretion of pituitary gonadotropins,
dose adjustments of exogenous gonadotropins may be necessary when used during controlled
ovarian hyperstimulation (COH).
Clinical Studies
The efficacy of Ganirelix Acetate Injection was established in two adequate and well-controlled
clinical studies which included women with normal endocrine and pelvic ultrasound parameters.
The studies intended to exclude subjects with polycystic ovary syndrome (PCOS) and subjects
with low or no ovarian reserve. One cycle of study medication was administered to each
randomized subject. For both studies, the administration of exogenous recombinant FSH
[Follistim® (follitropin beta for injection)] 150 IU daily was initiated on the morning of Day 2 or
3 of a natural menstrual cycle. Ganirelix Acetate Injection was administered on the morning of
Day 7 or 8 (Day 6 of recombinant FSH administration). The dose of recombinant FSH
administered was adjusted according to individual responses starting on the day of initiation of
Ganirelix Acetate. Both recombinant FSH and Ganirelix Acetate were continued daily until at
least three follicles were 17 mm or greater in diameter at which time hCG [Pregnyl® (chorionic
gonadotropin for injection, USP)] was administered. Following hCG administration, Ganirelix
Acetate and recombinant FSH administration were discontinued. Oocyte retrieval, followed by in
vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), was subsequently performed.
In a multicenter, double-blind, randomized, dose-finding study, the safety and efficacy of
Ganirelix Acetate Injection were evaluated for the prevention of LH surges in women undergoing
COH with recombinant FSH. Ganirelix Acetate Injection doses ranging from 62.5 mcg to 2000
mcg and recombinant FSH were administered to 332 patients undergoing COH for IVF (see
TABLE II). Median serum LH on the day of hCG administration decreased with increasing doses
of Ganirelix Acetate. Median serum E2 (17-estradiol) on the day of hCG administration was
1475, 1110, and 1160 pg/mL for the 62.5-, 125-, and 250-mcg doses, respectively. Lower peak
serum E2 levels of 823, 703, and 441 pg/mL were seen at higher doses of Ganirelix Acetate 500,
1000, and 2000 mcg, respectively. The highest pregnancy and implantation rates were achieved
with the 250-mcg dose of Ganirelix Acetate Injection as summarized in Table II.
3
TABLE II: Results from the multicenter, double-blind, randomized, dose-finding study to assess
the efficacy of Ganirelix Acetate Injection to prevent premature LH surges in women undergoing
COH with recombinant FSH.
No. subjects receiving
Ganirelix Acetate
No. subjects with ET†
No. of subjects with
LH rise  10 mIU/mL*
Serum LH (mIU/mL)
on day of hCG‡
5th–95th percentiles
62.5 mcg
31
Daily dose (mcg) of Ganirelix Acetate Injection
125 mcg
250 mcg
500 mcg
1000 mcg
66
70
69
66
2000 mcg
30
27
4
61
6
62
1
54
0
61
0
27
0
3.6
2.5
1.7
1.0
0.6
0.3
0.6–19.9
0.6–11.4
< 0.25–6.4
0.4–4.7
< 0.25–2.2
< 0.25–0.8
Serum E2 (pg/mL) on
day of hCG‡
5th–95th percentiles
1475
1110
1160
823
703
441
645–3720
424–3780
384–3910
279–2720
284–2360
166–1940
Vital pregnancy rate
per attempt, n (%)
per transfer, n (%)
Implantation rate (%)
7 (22.6)
7 (25.9)
14.2 (26.8)
17 (25.8)
17 (27.9)
16.3 (30.5)
25 (35.7)
25 (40.3)
21.9 (30.6)
8 (11.6)
8 (14.8)
9.0 (23.7)
9 (13.6)
9 (14.8)
8.5 (21.7)
2 (6.7)
2 (7.4)
4.9 (20.1)
(Protocol 38602)
*
‡

†

Following initiation of Ganirelix Acetate therapy. Includes subjects who have complied with daily injections
Median values
Mean (standard deviation)
ET: Embryo Transfer
As evidenced by ultrasound at 5–6 weeks following ET
Transient LH rises alone were not deleterious to achieving pregnancy with Ganirelix Acetate at
doses of 125 mcg (3/6 subjects) and 250 mcg (1/1 subjects). In addition, none of the subjects
with LH rises  10 mIU/mL had premature luteinization indicated by a serum progesterone above
2 ng/mL.
A multicenter, open-label, randomized study was conducted to assess the efficacy and safety of
Ganirelix Acetate Injection in women undergoing COH. Follicular phase treatment with
Ganirelix Acetate 250 mcg was studied using a luteal phase GnRH agonist as a reference
treatment. A total of 463 subjects were treated with Ganirelix Acetate by subcutaneous injection
once daily starting on Day 6 of recombinant FSH treatment. Recombinant FSH was maintained
at 150 IU for the first 5 days of ovarian stimulation and was then adjusted by the investigator on
the sixth day of gonadotropin use according to individual responses. The results for the Ganirelix
Acetate arm are summarized in Table III.
4
TABLE III: Results from the multicenter, open-label, randomized study to assess the efficacy
and safety of Ganirelix Acetate Injection in women undergoing COH.
Ganirelix Acetate 250 mcg
463
5.4 (2.0)
9.6 (2.0)
1190
373–3105
1.6
0.6–6.9
13
10.7 (5.3)
440
8.7 (5.6)
62.1%
399
2.2 (0.6)
6.0 (4.5)
No. subjects treated
Duration of GnRH analog (days)§¥
Duration of recombinant FSH (days)§¥
Serum E2 (pg/mL) on day of hCG‡
5th–95th percentiles
Serum LH (mIU/mL) on day of hCG‡
5th–95th percentiles
No. of subjects with LH rise  10 mIU/mL*
No. of follicles > 11 mm§¥
No. of subjects with oocyte retrieval
No. of oocytes¥
Fertilization rate
No. subjects with ET†
No. of embryos transferred¥
No. of embryos¥
Ongoing pregnancy rate§
per attempt, n (%)
per transfer, n (%)
Implantation rate (%)¥
94 (20.3)
93 (23.3)
15.7 (29)
(Protocol 38607)
*
Following initiation of Ganirelix Acetate therapy
Median values
§
Restricted to subjects with hCG injection
¥
Mean (standard deviation)
†
ET: Embryo Transfer

As evidenced by ultrasound at 12–16 weeks following ET

Includes one patient who achieved pregnancy with intrauterine induction
Some centers were limited to the transfer of  2 embryos based on local practice standards
‡
The mean number of days of Ganirelix Acetate treatment was 5.4 (2–14).
LH Surges
The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of
meiosis in the oocyte, and luteinization. In 463 subjects administered Ganirelix Acetate Injection
250 mcg, a premature LH surge prior to hCG administration, (LH rise  10 mIU/mL with a
significant rise in serum progesterone > 2 ng/mL, or a significant decline in serum estradiol)
occurred in less than 1% of subjects.
INDICATIONS AND USAGE
Ganirelix Acetate Injection is indicated for the inhibition of premature LH surges in women
undergoing controlled ovarian hyperstimulation.
CONTRAINDICATIONS
Ganirelix Acetate Injection is contraindicated under the following conditions:
• Known hypersensitivity to Ganirelix Acetate or to any of its components.
• Known hypersensitivity to GnRH or any other GnRH analog.
• Known or suspected pregnancy (see PRECAUTIONS).
5
WARNINGS
Ganirelix Acetate Injection should be prescribed by physicians who are experienced in infertility
treatment. Before starting treatment with Ganirelix Acetate, pregnancy must be excluded. Safe
use of Ganirelix Acetate during pregnancy has not been established (see
CONTRAINDICATIONS and PRECAUTIONS).
PRECAUTIONS
General
Special care should be taken in women with signs and symptoms of active allergic conditions.
Cases of hypersensitivity reactions, including anaphylactoid reactions, have been reported, as
early as with the first dose, during post-marketing surveillance (see ADVERSE REACTIONS).
In the absence of clinical experience, Ganirelix Acetate treatment is not advised in women with
severe allergic conditions.
The packaging of this product contains natural rubber latex which may cause allergic reactions
(see HOW SUPPLIED).
Information for Patients
Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of
treatment and monitoring procedures that will be required. The risk of possible adverse reactions
should be discussed (see ADVERSE REACTIONS).
Ganirelix Acetate should not be prescribed if the patient is pregnant.
Laboratory Tests
A neutrophil count  8.3 ( x 109/L) was noted in 11.9% (up to 16.8 x 109/L) of all subjects
treated within the adequate and well-controlled clinical trials. In addition, downward shifts
within the Ganirelix Acetate Injection group were observed for hematocrit and total bilirubin.
The clinical significance of these findings was not determined.
Drug Interactions
No formal drug-drug interaction studies have been performed.
Carcinogenesis and Mutagenesis, Impairment of Fertility
Long-term toxicity studies in animals have not been performed with Ganirelix Acetate Injection
to evaluate the carcinogenic potential of the drug. Ganirelix Acetate did not induce a mutagenic
response in the Ames test (S. typhimurium and E. coli) or produce chromosomal aberrations in in
vitro assay using Chinese Hamster Ovary cells.
Pregnancy
Ganirelix Acetate Injection is contraindicated in pregnant women. When administered from Day
7 to near term to pregnant rats and rabbits at doses up to 10 and 30 mcg/day (approximately 0.4
to 3.2 times the human dose based on body surface area), Ganirelix Acetate increased the
incidence of litter resorption. There was no increase in fetal abnormalities. No treatment-related
changes in fertility, physical, or behavioral characteristics were observed in the offspring of
female rats treated with Ganirelix Acetate during pregnancy and lactation.
6
The effects on fetal resorption are logical consequences of the alteration in hormonal levels
brought about by the antigonadotropic properties of this drug and could result in fetal loss in
humans. Therefore, this drug should not be used in pregnant women (see
CONTRAINDICATIONS).
Nursing Mothers
Ganirelix Acetate Injection should not be used by lactating women. It is not known whether this
drug is excreted in human milk.
Geriatric Use
Clinical studies with Ganirelix Acetate Injection did not include a sufficient number of subjects
aged 65 and over.
ADVERSE REACTIONS
The safety of Ganirelix Acetate Injection was evaluated in two randomized, parallel-group,
multicenter controlled clinical studies. Treatment duration for Ganirelix Acetate ranged from 1 to
14 days. Table IV represents adverse events (AEs) from first day of Ganirelix Acetate
administration until confirmation of pregnancy by ultrasound at an incidence of  1% in
Ganirelix Acetate-treated subjects without regard to causality.
TABLE IV: Incidence of common adverse events (Incidence  1% in Ganirelix Acetate-treated
subjects). Completed controlled clinical studies (All-subjects-treated group).
Adverse Events Occurring in  1%
Ganirelix Acetate N=794
% (n)
4.8 (38)
3.7 (29)
3.0 (24)
2.4 (19)
1.8 (14)
1.1 (9)
1.1 (9)
1.0 (8)
Abdominal Pain (gynecological)
Death Fetal
Headache
Ovarian Hyperstimulation Syndrome
Vaginal Bleeding
Injection Site Reaction
Nausea
Abdominal Pain (gastrointestinal)
During post-marketing surveillance, rare cases of hypersensitivity reactions, including
anaphylactoid reactions, have been reported, as early as with the first dose (see
PRECAUTIONS).
Congenital Anomalies
Clinical follow-up studies of 283 newborns of women administered Ganirelix Acetate Injection
were reviewed. There were three neonates with major congenital anomalies and 18 neonates with
minor congenital anomalies. The major congenital anomalies were: hydrocephalus/meningocele,
omphalocele, and Beckwith-Wiedemann Syndrome. The minor congenital anomalies were:
nevus, skin tags, sacral sinus, hemangioma, torticollis/asymmetric skull, talipes, supernumerary
digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia
umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis.
A subsequent analysis from an observational study in more than 1000 newborns compared the
incidence of congenital anomalies in newborns of women administered Ganirelix to historical
7
controls of a GnRH agonist. This analysis included the 283 newborns in the original studies. This
study demonstrated that the incidence of congenital anomalies in children born after COH
treatment in women using Ganirelix was comparable with that reported after a COH treatment
cycle using a GnRH agonist. The causal relationship between these congenital anomalies and
Ganirelix Acetate is unknown.
The incidence of congenital malformations after Assisted Reproductive Technology (ART) may
be slightly higher than after spontaneous conceptions. This slightly higher incidence is thought to
be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and
to the higher incidence of multiple gestations after ART.
OVERDOSAGE
There have been no reports of overdosage with Ganirelix Acetate Injection in humans.
DOSAGE AND ADMINISTRATION
After initiating FSH therapy on Day 2 or 3 of the cycle, Ganirelix Acetate Injection 250 mcg may
be administered subcutaneously once daily during the mid to late portion of the follicular phase.
By taking advantage of endogenous pituitary FSH secretion, the requirement for exogenously
administered FSH may be reduced. Treatment with Ganirelix Acetate should be continued daily
until the day of hCG administration. When a sufficient number of follicles of adequate size are
present, as assessed by ultrasound, final maturation of follicles is induced by administering hCG.
The administration of hCG should be withheld in cases where the ovaries are abnormally
enlarged on the last day of FSH therapy to reduce the chance of developing OHSS (Ovarian
Hyperstimulation Syndrome).
Directions for Using Ganirelix Acetate Injection
1. Ganirelix Acetate Injection is supplied in a sterile, prefilled syringe and is intended for
SUBCUTANEOUS administration only.
2. Wash hands thoroughly with soap and water.
3. The most convenient sites for SUBCUTANEOUS injection are in the abdomen around
the navel or upper thigh.
4. The injection site should be swabbed with a disinfectant to remove any surface bacteria.
Clean about two inches around the point where the needle will be inserted and let the
disinfectant dry for at least one minute before proceeding.
5. With syringe held upward, remove needle cover.
6. Pinch up a large area of skin between the finger and thumb. Vary the injection site a little
with each injection.
7. The needle should be inserted at the base of the pinched-up skin at an angle of 45–90° to
the skin surface.
8. When the needle is correctly positioned, it will be difficult to draw back on the plunger. If
any blood is drawn into the syringe, the needle tip has penetrated a vein or artery. If this
happens, withdraw the needle slightly and reposition the needle without removing it from
the skin. Alternatively, remove the needle and use a new, sterile, prefilled syringe. Cover
the injection site with a swab containing disinfectant and apply pressure; the site should
stop bleeding within one or two minutes.
8
9.
10.
11.
Once the needle is correctly placed, depress the plunger slowly and steadily, so the
solution is correctly injected and the skin is not damaged.
Pull the syringe out quickly and apply pressure to the site with a swab containing
disinfectant.
Use the sterile, prefilled syringe only once and dispose of it properly.
HOW SUPPLIED
Ganirelix Acetate Injection is supplied in:
Disposable, sterile, ready for use, prefilled 1 mL glass syringes containing 250 mcg/0.5
mL aqueous solution of Ganirelix Acetate closed with a rubber piston that does not
contain latex. Each Ganirelix Acetate sterile, prefilled syringe is affixed with a 27 gauge
x 1/2-inch needle closed by a needle shield of natural rubber latex. (See
PRECAUTIONS, General.)
Single syringe
NDC 0052-0301-51
Storage
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room
Temperature]. Protect from light.
Manufactured by: Vetter Pharma-Fertigung GmbH & Co. KG, Ravensburg, Germany
For patent information: www.merck.com/product/patent/home.html
Copyright © 1999, 2008 Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: 03/2016
uspi-mk8761-soi-1603r005
Rx only
9